Stabilized solid pharmaceutical preparation and method of producing the same

ABSTRACT

To stabilize the active ingredients, a caffeine is incorporated into a solid pharmaceutical preparation comprising a dextromethorphan and a phenylpropanolamine. The pharmaceutical preparation may further comprise ibuprofen. The active ingredients may be further stabilized, in combination with the incorporation of the caffeine, by grouping and incorporating separately each or suitably combined plural of the active ingredients into different groups or by minimizing the amount of any reducing sugar such as lactose. The solid pharmaceutical preparation is practically valuable since decomposition of each active ingredient with the lapse of time is remarkably suppressed and the active ingredients are stabilized for a longer period of time.

FIELD OF THE INVENTION

The present invention relates to a stabilized solid pharmaceuticalpreparation which is useful for therapy and prophylaxis of varioussymptoms of cold, and a method of producing the same. In more detail,the present invention relates to a stabilized solid pharmaceuticalpreparation which comprises a dextromethorphan as an antitussive and/oran expectorant, a phenylpropanolamine as a decongestant effective fornasal mucus and nasal congestion, and a caffeine, and which may furthercomprise ibuprofen as an antipuretic, analgesic and/or antiinflammatoryagent, and method of producing such preparations. Particularly, thepresent invention provides a stabilized pharmaceutical preparationcomprising a dextromethorphan, ibuprofen and a phenylpropanolamine whichare stabilized by further adding a caffeine to suppress or inhibitdecomposition of each of the active ingredients even when these activeingredients are incorporated or granulated in one group.

BACKGROUND OF THE INVENTION

Ibuprofen was first synthesized by Nicholson and Adamo in 1964,developed as a drug by Boots Pure Drug Co., Ltd., England, and has beenutilized mainly as an antipyretic, analgesic and/or antiinflammatoryagent. A phenylpropanolamine is a sympathomimetic drug havingephedrine-like pharmacological activities and therapeutic activities fornasal mucus and nasal congestion, and utilized as a drug for rhinitis innonproprietary drugs.

In JP-A-61-501913 corresponding to WO85/04589, and in W091/17746, thereare disclosed, for instance, pharmaceutical compositions of coldremedies comprising a nonsteroidal antiinflammatory agent such asibuprofen and the like as an analgesic ingredient, phenylpropanolaminehydrochloride as a decongestive ingredient, dextromethorphanhydrobromide as an antitussive and chlorpheniramine maleate as anantihistamine. These pharmaceutical preparations are prepared by mixingdextromethorphan, ibuprofen and phenylpropanolamine hydrochloridedirectly with lactose and/or other base without being subjected tostabilization.

As a result of various investigations for preparing general coldremedies having more excellent actions, the present inventors found thatpharmaceutical preparations comprising the dextromethorphan, thephenylpropanolamine (e.g. phenylpropanolamine hydrochloride, etc.) andfurther comprising ibuprofen are particularly favorable as coldremedies.

These pharmaceutical preparations, however, deteriorate or impair thestability of the active ingredients, and, thus, cause not only decreaseof the effective amounts of the ingredients but also change of theexternal appearance with the lapse of time.

More precisely, it is confirmed that decomposition ofphenylpropanolamine hydrochloride occurs by the reaction with some kindsof sugars, and by pH variation of a solution [R. H. Barry., J. Pharm.Sci., 71, No.1, Jan. 116-118, (1982)]. "Researches for incompatibilityof pharmaceutical preparations" [Ueda, Report of PharmacologicalResearch Institute of Toyama Pref., Vol. 1984/1985, p127-234, (1987)]discloses that phenylpropanolamine hydrochloride is incompatible withlysozyme chloride, potassium guaiacolsulfonate, dextromethorphanhydrobromide and so on.

On the other hand, since ibuprofen has a lower melting point of 75° C.,when ibuprofen is coexisted with other ingredients, it may frequentlycause melting point depression of the other ingredients. Further, apharmaceutical composition comprising ibuprofen and other ingredient haslow drug stability, thus it is liable to cause inactivation of activeingredients, change of external appearance and so on. For instance,"Incompatibility of ibuprofen granules" [Sato, Pharmacy, 27, 12, 73-78,(1976)] discloses that ibuprofen is incompatible with methylephedrine orsodium bicarbonate, and "Researches for incompatibility ofpharmaceutical preparations" [Ueda, Report of Pharmacological ResearchInstitute of Toyama Pref., Vol. 1984/1985, p127-234, (1987)] disclosesthat ibuprofen is incompatible with dl-chlorpheniramine maleate,ascorbic acid and so on.

Such problems as described above are particularly remarkable in apharmaceutical preparation comprising a phenylpropanolamine, adextromethorphan and ibuprofen. For example, in a pharmaceuticalpreparation containing dextromethorphan hydrobromide, ibuprofen andphenylpropanolamine hydrochloride as described in undermentionedExperimental Example 1, each of the ingredients is liable to bedecomposed at a high temperature with the passage of time. Particularly,the stability of phenylpropanolamine hydrochloride is impaired andchange of the external appearance occurs with incorporation of ibuprofenand dextromethorphan hydrobromide. Therefore, among pharmaceuticalpreparations comprising a dextromethorphan, ibuprofen, aphenylpropanolamine and the like, no successfully stabilizedpharmaceutical preparation having adequate utility has been developedyet.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provide a solidpharmaceutical preparation in which even though a dextromethorphan and aphenylpropanolamine being incompatible with each other are contained asactive ingredients, these active ingredients are stabilized therein, anda method of producing such a solid pharmaceutical preparation.

It is another object of the invention to provide a solid pharmaceuticalpreparation in which ibuprofen is further contained in addition to theingredients of a dextromethorphan and a phenylpropanolamine, and each ofthese active ingredients is stabilized, and a method of producing thesame.

It is still another object of the present invention to provide a solidpharmaceutical preparation in which inactivity of a dextromethorphan anda phenylpropanolamine, and further of ibuprofen and change of theexternal appearance of the pharmaceutical preparation with the passageof time are remarkably suppressed, and thus a longer quality assuranceperiod and a higher quality of products are obtained, and to provide amethod of producing such a pharmaceutical preparation.

It is a further object of the invention to provide a method forefficiently stabilizing a dextromethorphan and a phenylpropanolaminebeing incompatible with each other, and still more incompatible withibuprofen.

A still further object of the present invention is to provide a methodfor stabilizing the active ingredients, especially thephenylpropanolamine while maintaining high level stability for a longerduration of time.

Another object of the invention is to provide a solid pharmaceuticalpreparation useful for a cold remedy such as a general or complex coldremedy and the like, and to provide a method of producing such apreparation.

As a result of intensive investigations for stabilization of apharmaceutical preparation comprising a dextromethorphan, ibuprofen anda phenylpropanolamine, the inventors of the present invention found thatincorporation of a caffeine into the dextromethorphan, thephenylpropanolamine and, if necessary, ibuprofen unexpectedly increasesor improves the stability of these ingredients remarkably, and thatseparated incorporation of the phenylpropanolamine group furtherincreases the stability of the active ingredients and a stabilizedpharmaceutical preparation is thus obtained. The present invention hasbeen accomplished based on these findings and further researches.

Accordingly, the present invention provides (A) a stabilized solidpharmaceutical preparation comprising a dextromethorphan, aphenylpropanolamine and a caffeine, and these ingredients beingstabilized, and (B) the stabilized solid pharmaceutical preparationwhich further comprises ibuprofen. In these pharmaceutical preparations,the dextromethorphan and the phenylpropanolamine (for instance,phenylpropanolamine hydrochloride, etc.) may be incorporated intodifferent groups respectively, and ibuprofen may be compounded into thegroup of the dextromethorphan. Furthermore, in the phenylpropanolaminegroup, the content of a reducing sugar may be minimized or controlled tosuch an amount as to adversely affect the drug stability.

According to the method of the present invention, a caffeine isincorporated into a solid pharmaceutical preparation comprising adextromethorphan, a phenylpropanolamine, and if necessary, ibuprofen asactive ingredients to stabilize these active ingredients. In thestabilizing method, the morphology of the caffeine in the preparation isnot particularly restricted, and the stabilization of each activeingredient can be realized as far as the caffeine is coexistent in orwith the solid pharmaceutical preparation.

Further, in accordance with the method of the present invention, astabilized solid pharmaceutical preparation is produced by incorporatinga caffeine into a solid pharmaceutical preparation comprising adextromethorphan and a phenylpropanolamine. In this method, (i) agranulated preparation containing at least one active ingredientselected from the dextromethorphan, the phenylpropanolamine, thecaffeine and, if any, ibuprofen, and (ii) an optionally granulated otheractive ingredient(s) may be mixed. The plural active ingredients mayindividually be granulated to form a number of granulated preparationscorresponding to each of the active ingredients, or may form one or moreof granulated preparations wherein two or more of the active ingredientsare contained in one granulated preparation.

In this specification, the term "incorporating into different groups"refers to any and all cases in which, for example, the dextromethorphangroup and the phenylpropanolamine group are contained in the formwherein the contact with each other is inhibited or suppressed. The term"incorporating into different groups" may hereinafter be referred to as"grouping and incorporating separately". The term "phenylpropanolaminegroup" means a group containing the phenylpropanolamine. The term"granulated preparation" includes common products or preparationsgranulated by any means as well as fine granules, granules and pills.

Typical examples of the solid pharmaceutical preparation of the presentinvention include solid pharmaceutical preparations for oraladministration such as granulated preparations (for instance, finegranules, granules, pills and others), tablets, capsules and so on. Thepharmaceutical preparation of the invention is suitable for a coldremedy among others.

DETAILED DESCRIPTION OF THE INVENTION

The dextromethorphan used in the invention includes dextromethorphan(dextromethorphane) and salts thereof, for example, dextromethorphanhydrobromide, dextromethorphan.phenolphthalate and so on. Thephenylpropanolamine contained as another active ingredient in the solidpharmaceutical preparation of the invention includes anypharmacologically acceptable salts and may be, for example,phenylpropanolamine hydrochloride and others.

Examples of the caffeine include caffeine and derivatives therefrom suchas caffeine anhydride, caffeine monohydrate, caffeine citrate, caffeinesodium benzoate and the like.

The pharmaceutical preparation of the present invention may contain, ifdesired, other active ingredients than the dextromethorphan, ibuprofen,the phenylpropanolamine and the caffeine. These active ingredientsinclude, for example, antipyretic, analgesic and/or antiinflammatoryagents, antitussive and/or expectorants, bronchodilators, Chinesemedicine extracts, vitamins, gastric antacids and mucosa-protectingagents, minerals, amino acids and so on.

As the antipyretic, analgesic and/or antiinflammatory agents, there maybe mentioned, for example, acetaminophen, phenacetin, aspirin, aspirinaluminium, ethenzamide, aminopyrine, salicylamide, lactylphenetidin,isopropylantipyrine, sasapyrine, sodium salicylate, phenylbutazone,ketophenylbutazone, indomethacin, naproxen, ibufenac, serratiopeptidase,lysozyme chloride, mefenamic acid, alkaloids of belladonna extract andso on.

Examples of the antitussive and/or expectorants include chloperastinehydrochloride, codeines such as dihydrocodeine phosphate and codeinephosphate, oxymetebanol, eprazinone hydrochloride, tipepidine,tipepidine citrate, ephedrine hydrochloride, alloclamide hydrochloride,carbetapentane phenate, dibunate sodium, tipepidine hibenzate,chloperastine phendizoate, trimetoquinol hydrochloride, methoxyphenaminehydrochloride, dl-methylephedrine hydrochloride, noscapine, noscapinehydrochloride, dimemorfan or a salt thereof (e.g. dimemorfan phosphate,dimemorfan sulfate., etc.), bromhexine hydrochloride and so on.

The bronchodilators include, for example, ephedrine, theophylline,diphenhydramine or a salt thereof (e.g. diphenhydramine hydrochloride,etc.), chlorpheniramine or a salt thereof (e.g. chlorpheniramineD-maleate, etc.) and so on.

Examples of the Chinese medicine extract include an extract fromGlycyrrhizae radix, Polygala senega, Bupleuri radix, Cinnamomi cortex,Pherariae radix, Ephedrae herba, Schizonepetae herba, Forsythiaefructus, Armeniacae semen, Pinellae tuber, Paeoniae radix, Asiasriradix, Zingiberis rhizoma (ginger), Schisandrae fructus, Perillae herba,Ginseng radix, Aurantii nobilis pericarpium and the like.

As examples of vitamins, there may be mentioned vitamin B₁,fursultiamine, vitamin B₂, vitamin C and so on. Gastric antacids andmucosa-protecting agents include, for instance, magnesium hydroxide,magnesium oxide, aluminium hydroxide, aluminium sulfate, magnesiummetasilicate aluminate [e.g. Neusilin (Trade name)], magnesium silicatealuminate, synthetic hydrotalcite [e.g. ALCAMAC (Trade name)],coprecipitate of aluminium hydroxide and sodium bicarbonate [e.g.Kumulite (Trade name)], sucralfate and the like.

Where the pharmaceutical preparations of the present invention areutilized as cold remedies, these active ingredients are mixed usually inaccordance with a standard for a cold remedy described in DrugManufacturing Standard (revised in 1991, Yakugyo Jihosha Co., Ltd.,Japan).

As described above, since the dextromethorphan is chemicallyincompatible with the phenylpropanolamine, a combinational use of bothingredients lowers or decreases the stability of each of the activeingredients. Further, use of ibuprofen in combination with theingredients also tends to lower or decrease the stability of each activeingredients. Such combinations of the active ingredients particularlyimpairs the stability of the phenylpropanolamine. For stabilization ofsuch active ingredients being incompatible with each other, the caffeineis effectively and advantageously used.

In this invention, depending on the content, caffeine may exhibitpharmaceutical activities in addition to a stabilizing effect for theother active ingredients.

In the pharmaceutical preparation (A) in which the caffeine isincorporated with the dextromethorphan and the phenylpropanolamine asactive ingredients and ibuprofen is not contained, the effective amountof the caffeine so as to sufficiently stabilize the active ingredientsis, about 2 to 1,000 parts by weight, preferably about 4 to 750 parts byweight, and more preferably about 7 to 500 parts by weight relative to100 parts by weight of the total weight of the two active ingredients. Aparticularly preferred amount of the caffeine is about 10 to 300 partsby weight, preferably about 15 to 200 parts by weight and morepreferably about 25 to 100 parts by weight relative to 100 parts byweight of the total weight of the active ingredients.

The content of each active ingredient in the pharmaceutical preparation(A) may be selected from a suitable range. The pharmaceuticalpreparation usually comprises the dextromethorphan in a proportion ofabout 1 to 25% by weight and preferably about 2 to 20% by weight; thephenylpropanolamine in a proportion of about 2 to 35% by weight andpreferably about 5 to 30% by weight; and the caffeine in a proportion ofabout 1 to 60% by weight, preferably about 2 to 55% by weight, and morepreferably about 4 to 50% by weight, based on the total weight of thepharmaceutical preparation, and such preparation is economical andeffective.

For improving or enhancing the stability of the active ingredients inthe preparation (B) which comprises the caffeine in addition to thedextromethorphan, ibuprofen and the phenylpropanolamine as the activeingredients, the caffeine may preferably be contained in an amount ofabout. 1 to 1,000 parts by weight, preferably about 3 to 750 parts byweight and more preferably about 5 to 500 parts by weight relative to100 parts by weight of the total weight of the active ingredients. Atypically preferred proportion of the caffeine is about 5 to 200 partsby weight, preferably about 10 to 100 parts by weight and morepreferably about 12 to 50 parts by weight relative to 100 parts byweight of the total weight of the active ingredients.

The content of each of the active ingredients in the pharmaceuticalpreparation (B) can also be selected from a suitable range. Aneconomical and effective amount is based on the total weight of thepharmaceutical preparation, about 1 to 15% by weight and preferablyabout 2 to 10% by weight of the dextromethorphan; about 1 to 20% byweight and preferably about 2.to 15% by weight of thephenylpropanolamine; about 5 to 70% by weight, and preferably about 10to 60% by weight of ibuprofen; and about 1 to 80% by weight, preferablyabout 2 to 55% by weight and more preferably about 4 to 50% by weight ofthe caffeine.

In the pharmaceutical preparations (A) and (B), the amount of thecaffeine relative to each of the active ingredients can be selected fromthe range depending on the species of the active ingredients, and is,for example, about 0.5 to 1,000 parts by weight, preferably about 5 to500 parts by weight, more preferably about 10 to 300 parts by weight andpractically about 25 to 200 parts by weight relative to 100 parts byweight of each of the active ingredients.

The present invention is characterized in that even though thedextromethorphan and ibuprofen are incompatible with thephenylpropanolamine, the stability of these active ingredients can beincreased or improved by the caffeine. Therefore, the ingredients can beincorporated into the same one group, and thus an improved producibilitycan be obtained. That is, even when (a) the phenylpropanolamine, and (b)ibuprofen and the dextromethorphan each chemically incompatible with thephenylpropanolamine are incorporated or compounded into the same group,decrease of the stability of the active ingredients can greatly besuppressed or inhibited by means of incorporation of the caffeine intothe group, or coexistence of the caffeine with the group.

The pharmaceutical preparation in which the active ingredients arestabilized may also be obtained by (1) mixing a group containing thedextromethorphan and the phenylpropanolamine, and a group which issegregated from the former and contains the caffeine, or (2) mixing agroup containing the dextromethorphan, ibuprofen and thephenylpropanolamine, and a group which is separated from the former andcontains the caffeine.

Further, segregation of the dextromethorphan group from thephenylpropanolamine group into different groups is preferable forimproving the stability of the active ingredients. Ibuprofen mayfrequently be contained in the dextromethorphan group. In thisembodiment, for instance, (3) a method of separating or segregating eachingredient of the dextromethorphan, ibuprofen and thephenylpropanolamine from each other into different or separate groups,(4) a method of separating or segregating (a) the dextromethorphan groupor a group containing-the dextromethorphan and ibuprofen, from (b) thephenylpropanolamine group, or other methods can be employed. In theseembodiments, the caffeine may be incorporated or contained in any groupcontaining the active ingredient, for example, the phenylpropanolaminegroup, or may form a group being independent of another group containingthe active ingredient.

The stabilizing effects of the present invention can be achieved byaddition of the caffeine to a pharmaceutical preparation comprising thedextromethorphan, the phenylpropanolamine and, when necessary,ibuprofen.

In the manufacture of the preparation, ingredients having lowcompatibility with each other may respectively be incorporated orcontained in different groups. Usually, a carrier can advantageously beused for suppressing or inhibiting the contact of the ingredients havinglow compatibility with each other.

As the carriers, unless contrary to the objects of the invention andharm to the stability of the active ingredients, various conventionaladditives used in the manufacture of granulated preparations may beemployed. The carriers include various excipients such as lactose,sucrose, mannitol, corn starch, talc, crystalline cellulose [e.g. Avicel(Trade name) etc.], magnesium stearate, light silicic anhydride,magnesium carbonate, calcium carbonate, L-cysteine and the like; binderssuch as starch, alpha-starch, gelatin, powdered gum arabic,methylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium,hydroxypropylcellulose, hydroxypropylmethylcellulose,polyvinylpyrrolidone, pullulan, dextrin and so on; disintegrators suchas carboxymethylcellulose calcium [carmellose calcium, e.g. ECG 505(Trade name)], a low-substituted hydroxypropylcellulose, croscarmellosesodium [for example, Acdisol (Trade name)], etc.; surfactants includinganionic surfactants such as sodium alkylsulfates, and nonionicsurfactants such as polyoxyethylene-sorbitan fatty acid esters,polyoxyethylene-fatty acid esters and polyoxyethylene-castor oilderivatives; colorants; corrigents; adsorbents; preservatives; wettingagents; antistatic agents; disintegration retarders; and so on.

Among these carriers, at least an excipient and a binder are practicallyutilized, as well as a disintegrator.

As described above, in the pharmaceutical preparation of the invention,each ingredient of the dextromethorphan, ibuprofen and thephenylpropanolamine can be stabilized by incorporation of the caffeine.

In the preferred embodiments for the stabilization, at least oneingredient selected from the dextromethorphan (if desired withibuprofen) and the phenylpropanolamine is contained in a granulatedpreparation which is granulated with a carrier. In this case, theungranulated group of the active ingredient may be mixed with thegranulated preparation containing the other active ingredient and thecarrier.

Typically preferred embodiments include a solid pharmaceuticalpreparation in which the dextromethorphan, ibuprofen and thephenylpropanolamine are respectively grouped and segregated intodifferent or separate granulated preparations. Such preferredpharmaceutical preparation may be obtained by granulating (a) thedextromethorphan and ibuprofen in the same group and (b) thephenylpropanolamine in the other group into granulated preparationsrespectively. The caffeine may be added to each group or to any one ofthe groups. Further, the caffeine may form a granulated preparation ofan independent group separated from the granulated preparation(s)containing the active ingredient(s), so far as being coexistent with thegroups of the active ingredients. In such case, the solid pharmaceuticalpreparation can be obtained by mixing granulated preparations preparedby grouping and incorporating separately, for instance, a granulatedpreparation of the dextromethorphan group, a granulated preparation ofthe ibuprofen group, and a granulated preparation of thephenylpropanolamine group.

Preferred methods for "grouping and incorporating separately", that isfor incorporating into different or separate groups, include, other than(1) the abovementioned process which comprises granulating the activeingredients separately in different granulated preparations, and mixingthe preparations so as to lessen the contact area of the activeingredients, (2) a process of filling capsules with a mixture ofgranulated preparations grouped and incorporated separately, (3) aprocess of molding a mixture of granulated preparations grouped andincorporated separately into tablets, (4) a process of moldinggranulated preparations grouped and incorporated separately into tabletshaving two or more layers using a multi-layer tablet machine (forexample a machine manufactured by Kikusui Seisakusho Co., Ltd., etc.),in which each different adjacent layer contains a different group, (5) aprocess of molding granulated preparations grouped and incorporatedseparately into sandwich-type tablets having multiple layers, in which abuffering layer (for instance a thin layer) is interposed betweenadjacent layers and (6) a process of coating or encapsulating at leastone group of the active ingredients with a polymer to stabilize theactive ingredients by separation or segregation.

As practically preferred embodiments of such methods, there may bementioned the following processes.

For "grouping and incorporating separately", the dextromethorphan groupmay be prepared by a process which comprises mixing thedextromethorphan, and if necessary, other drug(s), and a carrier,preferably at least a binder and an excipient, and granulating themixture in accordance with a conventional manner. When wet fluidized-bedgranulation is employed, for example, the granulated preparation of thedextromethorphan group may be produced by mixing and charging suitableamount of additives such as an excipient, a disintegrator and the like,the dextromethorphan, and if desired, other drug(s), into afluidized-bed granulator, spraying a binder such as an aqueous solutionof hydroxypropylcellulose and the like into the granulator, and dryingthe granulation product to give a granulated preparation. Alternatively,a process which comprises extruding a kneaded product obtainable bystirring, kneading or the like, rounding or shaping the extruded productinto spherical form or structure with the use of a rounding means suchas a Marumerizer and drying the product.

The phenylpropanolamine group can also be obtained by the samegranulation procedures as in the dextromethorphan group except for usingthe phenylpropanolamine instead of the dextromethorphan.

In any cases where the active ingredients are grouped and incorporatedseparately, or where those are compounded into the same group, when thephenylpropanolamine group contains a large quantity of a reducing sugarsuch as lactose, sucrose and the like, the stability of thephenylpropanolamine is impaired. Therefore, preferably, the amount ofany reducing sugar contained in the phenylpropanolamine group isminimized to such an extent as to maintain the stability of thephenylpropanolamine. That is, the phenylpropanolamine group which doesnot contain a reducing sugar in such an amount as to harm or affectadversely the stability is preferable. Typical examples include (1) thephenylpropanolamine group which does not contain a reducing sugar, (2)even if containing a reducing sugar, the reducing sugar in thephenylpropanolamine group should be contained in a proportion of 10% byweight or less and preferably 7% by weight or less relative to the totalweight of granulated preparation of the phenylpropanolamine group, and(3) the phenylpropanolamine group which contains a sugar alcohol whichdoes not have a reducing hydroxyl group, such as mannitol maltitol andsorbitol instead of a reducing sugar.

The stability of the phenylpropanolamine can be improved by thecoexistent caffeine even when a reducing sugar is used with thephenylpropanolamine, and in some cases, with the dextromethorphan and/oribuprofen which are incompatible with the phenylpropanolamine.

In the pharmaceutical preparation comprising ibuprofen, ibuprofen may becompounded into the dextromethorphan group, or may be granulated in asimilar manner as in the dextromethorphan group to form a different orseparate group. The caffeine grouped and incorporated separately may (a)be incorporated, with the active ingredient, into each group to begranulated, (b) be compounded into any one group to be granulated, or(c) be granulated as a separate group in the same processes as above.

The pharmaceutical preparation comprising the active ingredientsincorporated into the same group may also be granulated in aconventional manner using the active ingredients and a carrier.

The granulation for producing the granulated preparation may be carriedout by use of a conventional granulation method. As examples of suchmethods, there may be mentioned a wet granulation such as spraygranulation, stirring granulation, fluidizing granulation, tumblinggranulation and tumbling-fluidizing granulation or a dry granulationsuch as compacting granulation using a powdery or granular binder.

The solid pharmaceutical preparation according to the present inventionmay be provided in a variety of dosage forms such as fine granules,granules, pills, tablets obtainable by compression-molding the finegranules or granules, and capsules obtainable by filling capsules withthe fine granules or granules. The mean particle size or diameter of thefine granules may be, for example, about 10 to 500 μm, preferably about100 to 500 μm. The mean particle size or diameter of the granules maybe, for example, about 500 to 1,500 μm.

The solid pharmaceutical preparations comprising a fine granule, agranule or a pill can be produced by (a) filling divided packages with agranulated preparation containing all active ingredients in the samegroup, or (b), in case of "grouping and incorporating separately" theactive ingredients, blending granulated preparations containing one ormore of the active ingredients (for instance, a granulated preparationof the dextromethorphan group which may further contain ibuprofen, agranulated preparation of the phenylpropanolamine group and, if desired,a granulated preparation of ibuprofen group), and filling dividedpackages with the mixture.

Capsules can be produced by means of filling directly, using acapsule-filling machine, capsules (c) with a granulated preparationcontaining all active ingredients in the same group or (d) with amixture of granulated preparations containing one or more of the activeingredients (e.g. a granulated preparation of the dextromethorphan groupwhich may further contain ibuprofen, a granulated preparation of thephenylpropanolamine group and, if necessary, a granulated preparation ofthe ibuprofen group) as well as by means of filling capsules with atleast two of granulated preparations in the form of two or more layerswhere each adjacent layer contains a different granulated preparationrespectively.

Tablets can be prepared by means of blending a granulated preparationcontaining the active ingredients in the same group, or granulatedpreparations containing one or more of the active ingredients (forexample, a granulated preparation of the dextromethorphan group whichmay further contain ibuprofen, a granulated preparation of thephenylpropanolamine group and, if desired, a granulated preparation ofthe ibuprofen group), and a carrier (for instance, an excipient, abinder, a disintegrator and the like), and compressing and molding themixture into a tablet.

Where the pharmaceutical preparation of the present invention is used asa cold remedy, the content of ibuprofen may be about 50 to 90% by weightand preferably about 60 to 80% by weight of the pharmaceuticallycommonly used amount of ibuprofen which is contained alone as an activeingredient. The proportion of the ibuprofen group is depends on the typeof the preparation, and may be, as the dose of ibuprofen for an adult,about 1 to 1,000 mg/day, preferably about 1 to 600 mg/day, and morepreferably about 30 to 500 mg/day. The preparation contains the otheringredients, as the dose per day for an adult, the dextromethorphangroup in such a proportion of about 1 to 100 mg, and preferably about 3to 75 mg; the phenylpropanolamine as phenylpropanolamine hydrochloridein an amount of about 0.5 to 200 mg, and preferably about 1 to 100 mg;the caffeine in a proportion of about 3 to 500 mg, and preferably about10 to 350 mg. The size of the pharmaceutical preparation selecteddepends on the amounts of the ingredients.

The pharmaceutical preparation of the present invention may be coatedwith a coating composition according to various objects. As the coatingcomposition, a composition such as a sugar coating compositioncomprising a sugar as a main component, and a film formable compositioncomprising a cellulosic base as a main component may be employed.

Components for such coating compositions include, for example, sugarssuch as granulated sugar and mannitol, gum arabic, talc,hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose,hydroxymethylcellulose, cellulose acetate phthalate,hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetatesuccinate, an acrylic acid copolymer, carboxymethylethylcellulose,polyvinyl acetal diethylaminoacetate, shellac, waxes and so on. Thesecomponents may be used in combination.

The coating composition may contain a conventional coating auxiliary. Assuch coating auxiliaries, there may be mentioned, for example, sugarssuch as lactose and mannitol, polyethylene glycol, polysorbate (e.g.Tween 80, etc.), colorants suchas titanium oxide, red iron oxide and soon.

The coating amount of the coating composition can be selected accordingto the type or species of the solid pharmaceutical preparation, and is,relative to the solid pharmaceutical preparation, about 0.1 to 30% byweight, and preferably about 0.5 to 10% by weight for tablets, about 0.1to 50% by weight, and preferably about 1 to 20% by weight for pills andgranules, and about 0.1 to 100% by weight, and preferably about 1 to 50%by weight for fine granules.

Coating can be carried out by a conventional manner such as pan coating,air-suspension or fluidized bed coating, tumbling coating or centrifugalcoating, or a combination of these procedures. When the coatingcomposition is a solution or a dispersion containing water or an organicsolvent, spray-coating can also be employed. The proportion of suchwater or organic solvent may for example be about 25 to 99% by weight.The type of organic solvent is not so critical, and includes, forexample, alcohols such as methanol, ethanol, isopropyl alcohol, etc.;ketones such as acetone etc.; and halogenated hydrocarbons such aschloroform, dichloromethane, trichloroethane and the like. Typicallypreferred examples of the solvent include water and/or an alcohol, andspecifically preferred is water.

Thus the solid pharmaceutical preparation of the present invention isstabilized wherein decomposition of the active ingredients with thepassage of time is suppressed. When the solid pharmaceutical preparationof the present invention is used for the therapy of cold as a commoncold remedy including a general or complex cold remedy for mammals suchas human beings, the solid pharmaceutical preparation such as a tablet,a granule and a capsule and the like may be administered orally by aconventional manner.

The following examples, comparative examples and experimental examplesare merely intended to illustrate the present invention in furtherdetail and should not be construed as defining the scope of theinvention.

EXAMPLES

Example 1

A high-shear type granulator (Vertical Granulator, FM-G25, manufacturedby Powrex Corporation, Japan) was charged with 1,350 g of ibuprofen(hereinafter may be referred to as IBU), 144 g of dextromethorphanhydrobromide (hereinafter may be abbreviated as DMP), 225 g ofphenylpropanolamine hydrochloride (hereinafter may be referred to asPPA), 225 g of caffeine anhydride (hereinafter may be abbreviated asCAF), 156 g of lactose, 600 g of crystalline cellulose, 150 g ofhydroxypropylcellulose (may be abbreviated as HPC-L, hereinbelow) and150 g of a low-substituted hydroxypropylcellulose (hereinafter may bereferred to as L-HPC). The charged material was granulated with stirringby adding 1,200 g of purified water to give granulated product.

The granulated product was extrusion-molding into fine cylindrical orcolumnar form using an extrusion-granulator (Domegran, DG-L1,manufactured by Fuji Paudal Co., Ltd., Japan) equipped with a punchingscreen of 0.35 mm φ, and rounded into spherical fine granules with useof Marumerizer (QJ-230, manufactured by Fuji Paudal Co., Ltd., Japan).The resultant spherical fine granules were dried at 40° C. in vacuo for10 hours to give 2,750 g of fine granules.

Example 2

The high-shear type granulator was charged with 1,125 g of IBU, 120 g ofDMP, 188 g of PPA, 114 g of lactose, 442 g of crystalline cellulose, 111g of HPC-L and 110 g of L-HPC, and the charged was granulated withstirring by adding 884 g of pure water, and dried at 40° C. in vacuo for14 hours. The dried product was comminuted by using a pulverizer (PowerMill, P-3S, manufactured by Showa Chemical Machinery Co., Ltd., Japan)provided with a punching screen 1.5 mm φ to give 2,010 g of a comminutedpowder (hereinbelow may be referred to as IDP).

On the other hand, a mixture of 1,500 g of CAF, 124 g of lactose, 464 gof crystalline cellulose, 116 g of HPC-L and 116 g of L-HPC was stirredand granulated while adding pure water using a high-rate stirring typegranulator, and 2,105 g of CAF comminuted powder was obtained from thegranulated product in the same procedures as in IDP comminuted powder.

A mixed powder was obtained by mixing 884 g of the IDP comminutedpowder, 116 g of the CAF comminuted powder, 333 g of crystallinecellulose, 60 g of L-HPC and 7 g of magnesium stearate with a tumblemixer (Tumbler Mixer, TM-15, manufactured by Showa Chemical MachineryCo., Ltd., Japan) for one minute, and the resultant mixed powder wascompression-molded with a rotary tablet machine (Correct 19K,manufactured by Kikusui Seisakusho Co., Ltd., Japan) with a punch of 9.5mm φ to prepare about 4,300 tablets (weight: 280 mg per tablet,lenticular form or shape, about 5 mm in thickness).

Example 3

The high-shear type granulator was charged with 1,350 g of IBU, 144 g ofDMP, 225 g of PPA, 225 g of CAF, 636 g of corn starch, 300 g ofcrystalline cellulose, 30 g of HPC-L and 90 g of ECG 505, and thecharged was stirred and granulated by adding 600 g of pure water. Theobtained product was extruded with an extrusion-granulator provided witha punching screen of 0.7 mm φ into cylindrical or columnar form, androunded with Marumerizer into spherical granules. The spherical granuleswere dried in vacuo at 40° C. for 10 hours to give 2,840 g of sphericalgranules. A capsule was filled with the spherical granules by using acapsule filling machine (Zanasi 6F, manufactured by IMA Co., Ltd.,Italy) to prepare a No. 1 capsule (total weight: 340 mg) having a longdiameter of about 19 mm.

Comparative Example 1

The procedures of Example 2 were followed without using the CAFcomminuted powder to give 4,200 lenticular tablets having a weight of275 mg per tablet and a thickness of about 5 mm.

Experimental example 1

A glass bottle was charged with the tablet obtained in Example 2 andComparative Example 1 respectively and sealed. After storage at 60° C.for 2 weeks, the content of each active ingredient was determined usinghigh performance liquid chromatography. The residual ratio relative tothe initial content of the ingredient before storage was calculatedaccording to the following formula, and the change of the externalappearance was observed with the naked eye. The results are set forth inTable 1.

Residual ratio (%)=(content after storage at 60° C./content beforestorage)×100

                  TABLE 1                                                         ______________________________________                                               Present Invention                                                                          Control                                                          (Tablet of Example 2)                                                                      (Tablet of Com. Ex. 1)                                    ______________________________________                                        IBU      98%            88%                                                   DMP      97%            83%                                                   PPA      92%            77%                                                   CAF      100%           --                                                    External no change      changed to yellow                                     appearance                                                                    ______________________________________                                    

As apparent from the Table 1, in the pharmaceutical preparation of thepresent invention, even when the active ingredients were not grouped orincorporated separately, the contents of IBU, DMP and PPA, and theexternal appearance are stabilized by addition of CAF.

Experimental Example 2

A glass bottle was charged with the fine granule of Example 1 or thecapsule of Example 3, and sealed. After being stored at 40° C., at 57%RH (relative humidity) for 4 weeks, the residual ratio of eachingredient was determined in the same manner as in Experimental Example1, and results are shown in Table

                  TABLE 2                                                         ______________________________________                                                    Example 1                                                                             Example 3                                                 ______________________________________                                        IBU            99%      101%                                                  DMP           101%      100%                                                  PPA           100%      100%                                                  CAF            99%      100%                                                  ______________________________________                                    

As clearly shown in Table 2, the pharmaceutical preparations of thepresent invention are stabilized and the content of each of the activeingredients is maintained at high level even when IBU, DMP, PPA and CAFare incorporated into the same group.

Example 4

To the high-shear type granulator were charged 1,350 g of IBU, 144 g ofDMP, 225 g of PPA, 250 g of CAF, 1.5 g of alkaloids of belladonnaextract, 241.5 g of corn starch, 420 g of crystalline cellulose, 84 g ofHPC-L and 84 g of L-HPC, and the charged was granulated with stirring byadding 1,000 g of pure water. The product was extruded into finecylindrical or columnar form by using an extrusion-granulator providedwith a punching screen of 0.9 mm φ, and rounded with Marumerizer intospherical granules. The obtained spherical granules were dried at 40° C.in vacuo for 16 hours to give 2,650 g of granules.

Comparative Example 2

IBU (1,350 g), DMP (144 g), PPA (225 g), crystalline cellulose (450 g)HPC-L (90 g) L-HPC (90 g) and lactose (651 g) were charged into thehigh-shear type granulator, and the charged was stirred and granulatedwith adding 1,000 g of pure water. The granulated products were extrudedinto fine cylindrical or columnar form with an extrusion-granulatorequipped with a punching screen of 0.7 mm φ, and rounded into sphericalgranules by using Marumerizer. The spherical granules were dried at 40°C. in vacuo for 16 hours to obtain 2,860 g of granules.

Examples 5 to 9

Granules were obtained in the same manner as in Comparative Example 2except that a part of lactose was substituted with CAF to adjust theproportion of CAF to 1% by weight (Example 5), 2% by weight (Example 6),3% by weight (Example 7), 4% by weight (Example 8) and 6% by weight(Example 9) based on the total weight of the granulated product.

Experimental Example 3

A glass bottle was charged with the granule obtained in ComparativeExample 2, or Examples 5 to 9 respectively. After sealing the bottle,the bottle was stored at 60° C. for 2 weeks, and the content of eachingredient was determined by a high performance liquid chromatographyand the residual ratio was calculated to give the results shown in Table3.

                  TABLE 3                                                         ______________________________________                                        CAF content Residual ratio of active ingredient                               in granule  IBU    DMP         PPA  CAF                                       ______________________________________                                        0%          90%    84%         82%  --                                        1%          94%    89%         83%  100%                                      2%          96%    92%         91%  100%                                      3%          96%    95%         93%  100%                                      4%          98%    96%         95%  100%                                      6%          99%    97%         96%  100%                                      ______________________________________                                    

What is claimed is:
 1. A stabilized solid pharmaceutical preparationwhich comprises a dextromethorphan and a phenylpropanolamine as activeingredients and a caffeine as stabilizer, the content of the caffeinebeing 10 to 300 parts by weight relative to 100 parts by weight of eachof said active ingredients.
 2. A stabilized solid pharmaceuticalpreparation according to claim 1, wherein the dextromethorphan and thephenylpropanolamine are contained in different granules separately.
 3. Astabilized solid pharmaceutical preparation according to claim 1,wherein the caffeine is contained in a proportion of 7 to 500 parts byweight relative to 100 parts by weight of the total weight of saidactive ingredients.
 4. A stabilized solid pharmaceutical preparationaccording to claim 3, which comprises 1 to 25% by weight of thedextromethorphan and 2 to 35% by weight of the phenylpropanolamine basedon the total weight of the pharmaceutical preparation, and 7 to 500parts by weight of the caffeine relative to 100 parts by weight of thetotal weight of said active ingredients.
 5. A stabilized solidpharmaceutical preparation according to claim 1, which comprises 2 to20% by weight of the dextromethorphan, 5 to 30% by weight of thephenylpropanolamine and 1 to 60% by weight of the caffeine based on thetotal weight of the pharmaceutical preparation.
 6. A stabilized solidpharmaceutical preparation according to claim 1, which comprises (1)granules wherein the caffeine is combined with the dextromethorphan andthe phenylpropanolamine, or (2) granules containing the dextromethorphanand the phenylpropanolamine and granules containing the caffeine.
 7. Astabilized solid pharmaceutical preparation according to claim 1, whichcomprises granules containing the dextromethorphan and granulescontaining the phenylpropanolamine, and the caffeine, wherein thecontent of any reducing sugar contained in the granules containing thephenylpropanolamine is minimized to such an extent as to maintain thestability of the phenylpropanolamine.
 8. A stabilized solidpharmaceutical preparation according to claim 1, which is a finegranule, a granule, a pill, a tablet or a capsule.
 9. A stabilized solidpharmaceutical preparation according to claim 1, which is apharmaceutical composition for a cold remedy.
 10. A stabilizing methodwhich comprises incorporating a stabilizing effective amount of acaffeine into a solid pharmaceutical preparation containing adextromethorphan and a phenylpropanolamine as active ingredients, theamount of caffeine being 7 to 500 parts by weight relative to 100 partsby weight of the total weight of active ingredients.
 11. A method ofproducing a stabilized solid pharmaceutical preparation which comprisesincorporating a stabilizing effective amount of a caffeine into a solidpharmaceutical preparation comprising a dextromethorphan and aphenylpropanolamine, the content of the caffeine being 10 to 300 partsby weight relative to 100 parts by weight of each of said activeingredients.
 12. A method of producing a stabilized solid pharmaceuticalpreparation according to claim 11, which comprises preparing granulescontaining both the dextromethorphan and the phenylpropanolamine, andgranules containing the caffeine, and mixing the former with the latter.13. A stabilized solid pharmaceutical preparation which comprises adextromethorphan and a phenylpropanolamine as active ingredients and acaffeine as stabilizer, wherein said preparation is composed of granulescomprising the dextromethorphan, the phenylpropanolamine and thecaffeine, and the content of the caffeine is 10 to 300 parts by weightrelative to 100 parts by weight of each of said active ingredients.